1. Field of the Invention
The present invention relates to novel O-acyloxime derivatives, a preparation method thereof and a pharmaceutical composition comprising the same for prevention and treatment of cardiovascular disease.
2. Description of the Prior Art
Recently, mortality from coronary heart disease (CHD) is significantly increased, and atherosclerosis is one of the major causes of death. Atherosclerosis is an inflammatory disease caused by accumulation of lipid and fibrin on the arterial wall, and the major causes of the disease are hypertension, smoking, obesity, increase of low-density lipoprotein (LDL) in plasma. However, another cause of the atherosclerosis may be inferred from the fact that more than 50% of patients have contracted atherosclerosis regardless of the above causes. According to the investigation result of 580 patients having coronary heart disease and 1,160 normal men, which is reported by the West of Scotland Coronary Prevention Study (WOSCOPS), lipoprotein-associated Phospholipase A2(Lp-PLA2)levels of the patients were significantly high compared to that of the normal men (N. Engl. J. Med., 2000, 343, 1148-1155), and it has been identified that Lp-PLA2 is an independent risk factor of coronary heart disease (Expert Rev. Mol. Diagn., 2002, 2, 17-22).
The molecular weight of Lp-PLA2 is 45 kDa. Lp-PLA2 is a secreted calcium-independent member type VII of phospholiphase A2 superfamily mainly formed by monocyte, macrophage, T-lymphocytes, and mast cells, and is known as an enzyme of platelet-activating factor acetylhydrolase (PAF-AH, EC 3.1.1.47) (Arterioscler. Thromb. Vasc. Biol., 1996, 16, 591-595). Additionally, 80% of Lp-PLA2 is bound to LDL, and the remainder is bound to high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) (Arterioscler. Thromb. Vasc. Biol, 1995, 75, 1764-1773).
Accumulation of LDL, particularly oxidized LDL, on the arterial wall is known as the most important initial step of atherosclerosis. Lp-PLA2 is bound to LDL in a latent state until LDL is oxidized or modified. As LDL is oxidized, Lp-PLA2 is activated and forms a large amount of lysophosphatidylcholine (lyso-PC) and free oxidized fatty acids by rapidly hydrolyzing the sn-2 fatty acid of oxidized phospholipid (Biochem. J., 1999, 338, 479-487). LDL is oxidized in intima and serves as a substrate of Lp-PLA2. Hydrolyzed products further accelerate chronic inflammation related to accumulation of macrophage, and a positive feedback mechanism of macrophage forming a large amount of Lp-PLA2 further accelerates progress of vascular disorder. Biological activity has not been defined completely yet, because structures of free oxidized fatty acids formed by Lp-PLA2 are not clearly identified. Fatty acids of micromolar concentration formed from ox-LDL are biologically inactive. However, in 1990s, reports on pro-inflammatory and pro-atherogenic role of lyso-PC, which is another decomposed product, were rapidly increased. For example, the reported roles are impairment of endothelium-dependent relaxation, inducement of vascular cell and intracellular adhesion molecules, activity as chemoattractant of monocyte and T-lymphocytes, suppressed production and release of endothelium-derived nitric oxide, inhibition of macrophage migration, toxicity at the concentration higher than 30-50 micromole, and release stimulation of arachidonic acid from endothelial cells (Curr. Opin. Pharmacol., 2001, 7,121-125).
Lp-PLA2 is an independent risk factor of coronary artery disease in the case of hypercholestrolemia patients, and is suggested as a pro-inflammatory agent, which is detected in macrophage of atherosclerotic lesions (Arterioscler. Thromb. Vasc. Biol., 1999, 19, 2909-2971). According to recent researches, the formation of fatty streak in Watanabe heritable hyperlipidemic rabbits, which is a model animal of atherosclerosis, is significantly decreased by dosing Lp-PLA2 inhibitor (Atherosclerosis, 2000, 151, 166). Therefore, inhibition of Lp-PLA2 activity is highlighted as a target for prevention and treatment of atherosclerosis (N. Engl. J. Med., 2000, 343,1148-55). Accordingly, research and development of Lp-PLA2 inhibitor will be very important for prevention and treatment of atherosclerosis.
GlaxoSmithKline isolated a series of novel inhibitors of Lp-PLA2 from the culture broths of Pseudomonas fluorescens (J. Antibiotics, 2000, 53, 664-669). A potent, orally active Lp-PLA2 inhibitor, SB-480848, has been developed from their synthetic derivatives, and SB-480848 is currently in a phase II clinical study.
Through researches on novel drugs for treatment of hyperlipidemia and atherosclerosis, the inventors have synthesized O-acyloxime derivatives, and completed the present invention by identifying that these compounds have inhibitory effects on Lp-PLA2.